The filarioid nematodes Wuchereria bancrofti, Brugia malayi, and B. timori are mosquito-transmitted pathogens responsible for lymphatic filariasis in approximately 80 million humans throughout the tropics and subtopics, with an additional 750 million people at risk. Control efforts have been seriously hampered by emergence of pesticide resistance in mosquito populations, environmental concerns over pesticide applications, lack of progress in vaccine development, and the limited array of available pharmacological agents for prophylaxis or treatment. The ultimate objective of this research is to determine, at the genetic level, those factors that influence the vector competence of mosquitoes for filarial worms and to use this information to develop novel control strategies aimed at disrupting the life cycle of mosquito-borne filariasis. The research described primarily examines the mosquito, Aedes aegypti, and its genetic relationship with the filarial worm, B. malayi, as a model system for elucidating genetic control mechanisms, because of the wealth of knowledge available concerning the genetics of this vector. Additionally, some aspects of the proposed research include a primary vector for W. bancrofti, Culex pipiens quinquefasciatus. The specific aims of this project are (1) isolate genes that influence filarial worm susceptibility using map-based cloning techniques, (2) isolate molecules that are tightly associated with mosquito strains that are susceptible or refractory to filarial worm development using in vivo amino acid labeling and differential display PCR methodologies, (3) obtain DNA clones of inducible immune peptides and polypeptides identified from Ae. aegypti through a collaborative effort with a research group at the Institute of Molecular and Cellular Biology, Strasbourg, France, (4) construct a RFLP linkage map of Cx. p. quinquefasciatus, using markers developed previously for Ae. aegypti, and use this map to identify linkage associations between these markers and the genes that influence susceptibility/refractoriness of Cx. p. quinquefasciatus to B. malayi development, and (5) assess the potential of candidate genes, identified in specific aims 1-4, to positively or negatively influence the development of filaroid nematodes using the Sindbis or AeDNV virus expression systems in cooperation with Colorado State university.